Melanomas are aggressive, frequently metastatic tumors derived from either melanocytes or melanocyte related nevus cells (“Cellular and Molecular Immunology” (1991) (eds) Abbas A. K., Lechtman, A. H., Pober, J. S.; W. B. Saunders Company, Philadelphia: pages 340-341). Melanomas make up approximately three percent of all skin cancers and the worldwide increase in melanoma is unsurpassed by any other neoplasm with the exception of lung cancer in women (“Cellular and Molecular Immunology” (1991) (eds) Abbas, A. K., Lechtiman, A. H., Pober, J. S.; W. B. Saunders Company Philadelphia pages: 340-342; Kirkwood and Agarwala (1993) Principles and Practice of Oncology 7:1-16). Even when melanoma is apparently localized to the skin, up to 30%; of the patients will develop systemic metastasis and the majority of these will die (Kirkwood and Agarwala (1993) Principles and Practice of Oncology 7:1-16). Classic modalities of treating melanoma include surgery, radiation and chemotherapy. In the past decade immunotherapy and gene therapy have emerged as new and promising methods for treating melanoma (Biologic Therapy of Cancer, 2nd ed. (1995) Devita, V. T., Hellman, S, and Rosenberg, S. A., eds; J. B. Lippincott Co., Philadelphia).
Shared melanoma-associated antigens (Ag) expressed among a variety of melanoma patients can be recognized by cytotoxic CD8+ T lymphocytes derived from melanoma patients. In short-term lysis assays, cytotoxic T lymphocytes (CTL) grown from in vitro sensitized peripheral blood lymphocytes (PBL) or lymph node lymphocytes, or from lymphocytes infiltrating metastatic melanoma lesions, have been shown to recognize autologous and MHC class I compatible allogeneic melanomas but not HLA-matched nonmelanoma tumors, lymphoblasts, or cultured fibroblasts (Darrow, D. L., Slingluff, C. L., & Siegler, H. F. (1989.) J. Immunol. 142, 3329-3335; Hom, S. S., et al. (1991) J. Immunother. 10, 153-164). Similar recognition patterns have been observed by measuring cytokine secretion from tumor infiltrating lymphocytes (TIL) cocultivated with autologous or HLA-matched allogeneic tumor stimulators (Hom, S. S., et al. (1993) J. Immunother. 13, 18-30). Recently, melanoma-specific HLA-A2 restricted CTL clones have been shown to recognize cultured normal melanocytes as well as their malignant counterparts, suggesting that shared melanoma antigens can be lineage specific (Anichini, A., et al. (1993) J. Exp. Med. 177, 989-998). To date, several class I-restricted melanoma-associated antigens have been molecularly defined (Van Der Bruggen, P., et al. (1991) Science 254, 1643-1647; Brichard, V., et al. (1993) J. Exp. Med. 178, 489-495; Kawakami, Y., et al. (1994) Proc. Natl. Acad. Sci. USA. 91, 3515-3519; Bakker, A. B. H., et al. (1994) J. Exp. Med. 179, 1005-1009; Kawakami, Y., et al. (1994) Proc. Natl. Acad. Sci. USA. 91,6458-6462; Gaugler B., et al. (1994) J. Exp. Med. 179, 921-930). These antigens and derivative class I-restricted peptides 8 to 10 amino acids in length are currently being developed as clinical vaccines to stimulate CD8+ T cell responses against melanoma.
While animal models of malignant and viral diseases have shown the importance of CD8+ T cells in the effector phase of the immune response, the CD4+ helper arm has been shown to mediate critical priming and effector functions as well. T cell receptors on CD4+ T cells recognize a complex consisting of an antigenic peptide in conjunction with an MHC Class II molecule. Unlike peptides binding to MHC class I molecules, which are restricted in length from 8-10 amino acids, the antigenic peptides that bind Class II range from about 10 to about 34 amino acids in length and even entire proteins. (Chicz, R. M. et al (1993) J. Exp. Med. 178, 27-47; Sette, A. et al (1989) J. Immunol 143, 1265-1267.) This is due to the structure of the peptide binding groove in MHC class II molecules, which is open at both ends and allows for overhang of longer peptides outside of the critical binding core. In contrast, the peptide binding groove in MHC class I molecules is closed at both ends, strictly limiting the length of possible binding peptides. (Brown, J. H. et al (1993) Nature 364, 33-39).
Strong and long lasting immunity depends in part on CD4+ helper T cell functions. Therefore the identification of Class II-restricted melanoma antigens will broaden the immunotherapeutic approaches to treating and/or prophylaxing against melanoma.